Sabino Veintemillas-Verdaguer

The preparation of magnetic nanoparticles for applications in biomedicine

This review is focused on describing state-of-the-art synthetic routes for the preparation of magnetic nanoparticles useful for biomedical applications. In addition to this topic, we have also described in some detail some of the possible applications of magnetic nanoparticles in the field of biomedicine with special emphasis on showing the benefits of using nanoparticles. Finally, we have addressed some relevant findings on the importance of having well-defined synthetic routes to produce materials not only with similar physical features but also with similar crystallochemical characteristics.

Progress in the preparation of magnetic nanoparticles for applications in biomedicine

This review summarizes recent advances in synthesis routes for quickly and reliably making and functionalizing magnetic nanoparticles for applications in biomedicine. We put special emphasis on describing synthetic strategies that result in the production of nanosized materials with well-defined physical and crystallochemical characteristics as well as colloidal and magnetic properties. Rather than grouping the information according to the synthetic route, we have described methods to prepare water-dispersible equiaxial magnetic nanoparticles with sizes below about 10 nm, sizes between 10 and 30 nm and sizes around the monodomain–multidomain magnetic transition. We have also described some recent examples reporting the preparation of anisometric nanoparticles as well as methods to prepare magnetic nanosized materials other than iron oxide ferrites, for example Co and Mn ferrite, FePt and manganites. Finally, we have described examples of the preparation of multicomponent systems with purely inorganic or organic–inorganic characteristics.

The influence of surface functionalization on the enhanced internalization of magnetic nanoparticles in cancer cells

The internalization and biocompatibility of iron oxide nanoparticles surface functionalized with four differently charged carbohydrates have been tested in the human cervical carcinoma cell line (HeLa). Neutral, positive, and negative iron oxide nanoparticles were obtained by coating with dextran, aminodextran, heparin, and dimercaptosuccinic acid, resulting in colloidal suspensions stable at pH 7 with similar aggregate size. No intracellular uptake was detected in cells incubated with neutral charged nanoparticles, while negative particles showed different behaviour depending on the nature of the coating. Thus, dimercaptosuccinic-coated nanoparticles showed low cellular uptake with non-toxic effects, while heparin-coated particles showed cellular uptake only at high nanoparticle concentrations and induced abnormal mitotic spindle configurations. Finally, cationic magnetic nanoparticles show excellent properties for possible in vivo biomedical applications such as cell tracking by magnetic resonance imaging (MRI) and cancer treatment by hyperthermia: (i) they enter into cells with high effectiveness, and are localized in endosomes; (ii) they can be easily detected inside cells by optical microscopy, (iii) they are retained for relatively long periods of time, and (iv) they do not induce any cytotoxicity.

Effect of Nanoparticle and Aggregate Size on the Relaxometric Properties of MR Contrast Agents Based on High Quality Magnetite Nanoparticles

Colloidal dispersions of monodispersed and high-crystalline magnetite nanoparticles have been used to establish a relationship between magnetic properties and magnetic resonance (MR) relaxometric parameters in vitro. Magnetite nanoparticles with diameters between 4 and 14 nm were synthesized by thermal decomposition of Fe(acac)3 in different organic solvents and transformed to hydrophilic by changing oleic acid for dimercaptosuccinic acid (DMSA). A final treatment in alkaline water was critical to make the suspension stable at pH 7 with xi-potential values of -45 mV and hydrodynamic sizes as low as 50 nm. Samples showed superparamagnetic behavior at room temperature, which is an important parameter for biomedical applications. Susceptibility increased with both particle and aggregate size, and for particles larger than 9 nm, the aggregate size was the key factor controlling the susceptibility. Relaxivity values followed the same trend as the suspension susceptibilities, indicating that the aggregate size is an important factor above a certain particle size governing the proton relaxation times. The highest relaxivity value, r2=317 s(-1) mM(-1), much higher than those for commercial contrast agents with similar hydrodynamic size, was obtained for a suspension consisting of 9 nm particles and 70 nm of hydrodynamic size, and it was assigned to the higher particle crystallinity in comparison to particles prepared by coprecipitation. Therefore, it can be concluded that in addition to the sample crystallinity, both particle size and aggregate size should be considered in order to explain the magnetic and relaxivity values of a suspension.

Continuous production of γ-Fe2O3 ultrafine powders by laser pyrolysis

Pure γ-Fe2O3 particles were prepared by a continuous process from cw CO2 laser induced pyrolysis of a 30% solution of iron pentacarbonyl in isopropanol with a yield of about 50% and an average productivity of 0.05 g/h. From TEM the particle size is 5±2 nm with a low degree of aggregation, which agrees with the size obtained from the width of the X-ray diffraction peaks. The nanoparticles seem to be well crystallised according to his infrared spectrum. Moreover, superparamagnetic behaviour was observed at room temperature with a saturation magnetisation value of 30.5 emu/g.

Comparative study of ferrofluids based on dextran-coated iron oxide and metal nanoparticles for contrast agents in magnetic resonance imaging

Colloidal suspensions of iron oxide and metal iron nanoparticles prepared by laser pyrolysis have been obtained by coating the particles with dextran in an aqueous media giving rise to biocompatible ferrofluids. The structural characteristics of the powders and the size of the particles and the aggregates in the colloidal suspensions have been analysed and correlated with the magnetic properties of both solids and fluids. For the first time, to our knowledge, a stable ferrofluid based on metal particles (<10?nm) has been obtained with aggregate sizes of ?nm. In comparison to iron oxide based products, this material exhibits higher saturation magnetization (45?emu?g?1) and susceptibilities (4000?emu/g?T). In addition, the nuclear magnetic resonance response of the ferrofluids has been measured in order to gain information about the influence of the crystallochemical and magnetic properties on their relaxation behaviour. The main parameter affected by the presence of the magnetic nanoparticles is the transversal relaxation time T2 and the corresponding relaxivity R2 value that is of the order of 400?(mmol/l)?1?s?1. It has been shown that R2 value increases not only by using iron metal instead of iron oxide but also by increasing the crystal size of the particles. From this study an evaluation of the possibilities of these materials as contrast agents for magnetic resonance imaging has been made.

Short-chain PEG molecules strongly bound to magnetic nanoparticle for MRI long circulating agents

This study developed an approach for the synthesis of magnetic nanoparticles coated with three different polyethylene glycol (PEG)-derived molecules. The influence of the coating on different properties of the nanoparticles was studied. Magnetite nanoparticles (7 and 12 nm in diameter) were obtained via thermal decomposition of a coordination complex as an iron precursor to ensure nanoparticle homogeneity in size and shape. Particles were first coated with meso-2,3-dimercaptosuccinic acid by a ligand exchange process to remove oleic acid, followed by modification with three distinct short-chain PEG polymers, which were covalently bound to the nanoparticle surface via 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride activation of the carboxylic acids. In all cases, colloidal suspensions had hydrodynamic sizes <100 nm and low surface charge, demonstrating the effect of PEG coating on the aggregation properties and steric stabilization of the magnetic nanoparticles. The internalization and biocompatibility of these materials in the HeLa human cervical carcinoma cell line were tested. Cells preincubated with PEG-coated iron nanoparticles were visualized outside the cells, and their biocompatibility at high Fe concentrations was demonstrated using a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Finally, relaxivity parameters (r1 and r2) were used to evaluate the efficiency of suspensions as magnetic resonance imaging contrast agents; the r2 value was similar to that for Resovist and up to four times higher than that for Sinerem, probably due to the larger nanoparticle size. The time of residence in blood of the nanoparticles measured from the relaxivity values, and the Fe content in blood was doubled for rats and rabbits due to the PEG on the nanoparticle surface. The results suggest that this PEGylation strategy for large magnetic nanoparticles (>10nm) holds promise for biomedical applications.

Ultrasmall Iron Oxide Nanoparticles for Biomedical Applications: Improving the Colloidal and Magnetic Properties

A considerable increase in the saturation magnetization, M(s) (40%), and initial susceptibility of ultrasmall (<5 nm) iron oxide nanoparticles prepared by laser pyrolysis was obtained through an optimized acid treatment. Moreover, a significant enhancement in the colloidal properties, such as smaller aggregate sizes in aqueous media and increased surface charge densities, was found after this chemical protocol. The results are consistent with a reduction in nanoparticle surface disorder induced by a dissolution-recrystallization mechanism.

Liver and brain imaging through dimercaptosuccinic acid-coated iron oxide nanoparticles

BACKGROUND & AIM Uptake, cytotoxicity and interaction of improved superparamagnetic iron oxide nanoparticles were studied in cells, tissues and organs after single and multiple exposures. MATERIAL & METHOD We prepared dimercaptosuccinic acid-coated iron oxide nanoparticles by thermal decomposition in organic medium, resulting in aqueous suspensions with a small hydrodynamic size (< 100 nm), high saturation magnetization and susceptibility, high nuclear magnetic resonance contrast and low cytotoxicity. RESULTS In vitro and in vivo behavior showed that these nanoparticles are efficient carriers for drug delivery to the liver and brain that can be combined with MRI detection.

Effect of the process conditions on the structural and magnetic properties of γ-Fe2O3 nanoparticles produced by laser pyrolysis

Pure and uniform γ-Fe2O3 nanoparticles between 4 and 7 nm, have been prepared by a continuous process based on ethylene sensitised laser pyrolysis of iron pentacarbonyl vapours in an oxidant atmosphere. In this paper the effect of the laser power and oxygen proportion on the properties of the maghemite nanoparticles has been investigated.